: The objective of the proposed research is the testing and development of a new concept for the design of inhibitors of HIV protease, an enzyme that has been demonstrated to be essential for the replication of HIV. A series of inhibitors are proposed, the structures of which incorporate elements that are known to induce binding to the protease, as well as a novel electrophilic aziridinyl moiety that will serve to react covalently with residues of the protease that appear to be conserved. The design of the inhibitors, the first phase of which has been completed as preliminary work, has employed molecular graphics, starting with the crystallographically-determined coordinates of a complex of the protease with a known noncovalent inhibitor. The structure of the noncovalent inhibitor serves as the starting point for the design of the covalent inhibitors, so that molecular graphics-based design represents a relatively small perturbation of a known structure. The synthesis and evaluation of the proposed inhibitors is described. The results of enzyme inhibition studies will be used to refine the molecular-graphics design of inhibitor structures. Chemical model systems are also proposed to test the use of aziridines as electrophilic enzyme-modifying reagents.